Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602133 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific symbol: MH1

Mapping: By analysing Illumina Bovine 50k Beadchip genotype data from 47,878 Holstein, 16,833 Montbéliarde and 11,466 Normande cattle in the French genomic selection database, Fritz et al. (2013) identified 34 common (>1%) haplotypes that have a significant deficit (P<10^-4) of homozygotes in live animals, and which are, therefore, each likely to harbour a deleterious mutation. Three of these haplotypes, namely BY (Brachyspina; OMIA 000151-9913), HH1 (OMIA 000001-9913) and HH3 (OMIA 001824-9913), had been reported by VanRaden et al. (2011; J Dairy Sci 94:6153-61). Following the convention of naming such haplotypes with a first letter indicating breed, a second letter H for haplotype, followed by a sequential number, Fritz et al. (2013) named their 14 new Holstein haplotypes as HH4 to HH17, their 11 Montbéliarde haplotypes as MH1 to MH11, and their six Normande haplotypes as NH1 to NH6. Analyses of reproductive data indicated that nine of the 34 haplotypes have a significant effect on fertility, including six of the newly identified haplotypes, namely HH4, HH5, HH6, MH1, MH2 and NH5. This present OMIA entry is for MH1, which is located in chromosome BTA19, at 27.6–29.4Mb (UMD 3.1 genome assembly) (Fritz et al., 2013).

Molecular basis: For eight of the nine haplotypes with a significant effect on calving rate (see Mapping section), Fritz et al. (2013) searched for causal mutations via whole-genome sequence data from 25 Holstein, 11 Montbéliarde and nine Normande bulls which had made major contributions to their breed. Specifically, they filtered "for mutations that were (a) located at+or –6 Mb from the detected haplotype (b) carried in the heterozygous state by the carrier bulls and (c) absent from the non carrier bulls from the three breeds" and then examined identified polymorphisms for their likely effect on protein structure and function. For MH1, Fritz et al. (2013) provided strong evidence for a candidate causal mutation, namely a nonsense mutation (g.27956790C>T; UMD 3.1 genome assembly) in the SHBG gene (which encodes sex-hormone binding globulin), leading to p.Q52X. Reinartz and Distl (2016) reported this mutant occurring in Vorderwald cattle with Montbéliarde ancestry, including in one live animal that is homozygous for this mutant. The one live animal homozygous for this supposedly lethal variant reported by Reinartz and Distl (2016) was reinforced by an extensive study by Michot et al. (2017) who, in the results of genotyping 128,743 Montbéliarde cattle, "identified 242 homozygous carriers for the SHBG nonsense mutation (for 650 expected homozygotes), suggesting that it was not the causative mutation for MH1-linked embryonic lethality." Subsequent fine mapping of the MH1 region excluded SHBG as a candidate and eventually led Michot et al. (2017) to "g.28511199C>T (rs455876205) . . . PFAS p.R1205C" as the likely causal variant. Supporting evidence included "The absence of homozygous mutants among tens of thousands of genotyped animals, the perfect conservation of the affected residue among eukaryotes, and the critical function of PFAS and of the de novo purine synthesis pathway".

Clinical features: The effect of this haplotype is a reduction of 5.8% in heifer calving rate and of 4.84% in cow calving rate (Fritz et al., 2013).

Prevalence: The MH1 haplotype occurs with a frequency of 9.0% in the 16,833 Montbéliarde adult cattle sampled by Fritz et al. (2013), but never as a homozygote. Reinartz and Distl (2020) "genotyped 354 Vorderwald cattle for the PFAS variant, resulting in 41 heterozygous individuals and a T allele frequency of 0.058." They also reported that "The earliest animal with a heterozygous PFAS genotype was 1 of 5 migrant Montbéliarde bulls, and this bull was the most likely origin of the deleterious PFAS allele in Vorderwald cattle. All Vorderwald cattle under study born before introgression of this Montbéliarde bull were homozygous wild type. In addition, all 41 heterozygous Vorderwald cattle had genetic contributions from this Montbéliarde bull, whereas in 74 Vorderwald cattle without genes from Montbéliarde bulls, the PFAS T allele was not observed. In a sample of actual German Fleckvieh the PFAS T allele could be found at a very low frequency."

Breeds: Montbéliarde (Cattle) (VBO_0000306), Vorderwälder, Germany (Cattle) (VBO_0004645).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: